TPI 2020; 9(2): 72-80 diagnosis and treatment of birth defects … · Comparative study on...

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The Pharma Innovation Journal 2020; 9(2): 72-80

ISSN (E): 2277- 7695

ISSN (P): 2349-8242

NAAS Rating: 5.03

TPI 2020; 9(2): 72-80

© 2020 TPI

www.thepharmajournal.com

Received: 18-12-2019

Accepted: 22-01-2019

Iffat Ara Zabeen

Department of Pharmacy,

Faculty of Life Science,

University of Development

Alternative, Dhaka, Bangladesh

Md. Mehdi Hasan

1. Department of Pharmacy,



Alternative, Dhaka,

Bangladesh

2. Department of Pharmacy,

Faculty of Health Science,

Northern University

Bangladesh, Dhaka,

Bangladesh

Zubaida Khatun





Corresponding Author:

Iffat Ara Zabeen





Comparative study on strategies for the prevention,

diagnosis and treatment of birth defects

Iffat Ara Zabeen, Md. Mehdi Hasan and Zubaida Khatun

Abstract As child mortality rates overall are decreasing, non-communicable conditions, such as genetic disorders,

constitute an increasing proportion of child mortality, morbidity and disability. To date, policy and public

health programmes have focused on common genetic disorders. Rare single gene disorders are an important

source of morbidity and premature mortality for affected families. About 2-3% of all live births suffer

from congenital abnormality globally and 70% of those are preventable through community genetics

services. The estimated prevalence of congenital abnormalities is about 2-4% in live births along with still

born and aborted fetus. As child mortality rates overall are decreasing, non-communicable conditions, such

as genetic disorders, constitute an increasing proportion of child mortality, morbidity and disability. To

date, policy and public health programmers have focused on common genetic disorders. Rare single gene

disorders are an important source of morbidity and premature mortality for affected families. This review

will provide a context for the general evaluation of a neonate with congenital anomalies, including

adaptation of the most precise terminology, definition of major and minor anomalies, and the determination

of whether the anomalies are the result of a sequence, deformation, disruption, or malformation. Practical

tools, including a concise family history, nutritional implication, pregnancy history, and the effects of

assisted reproductive technologies are also presented.

Keywords: Prevention, diagnosis, and treatment of birth defects

Introduction

The two initial weeks after fertilization, in which the zygote is undergoing mitotic cell division

is called the ‘all-or-nothing’ phase; in case a contact with a teratogenic agent occurs, it can result

either in spontaneous abortion or in a normal embryo-fetal development. If teratogenic expo-

sure occurs between the 3rd and 8th week of gestation, a period in which most of the

morphological structures develop, it can lead to considerable phenotypical changes in the em-

bryo, such as alterations in the central nervous system, limbs and face. From the 9th week of

gestation some organs are still developing, like external genitalia and brain, and exposure to

teratogens can culminate in functional abnormalities. However most morphological

characteristics are preserved from this phase onward.

A Congenital malformation is a gross structural deformity present at birth. Its incidence is about

2.5% in all the infants born. However, only half of these deformities are apparent at the time of

delivery, most of the remaining come to light during the first postnatal year. The term congenital

deformity is reserved for a minor congenital disorder such as a deformed finger or ear-lobe.

Individuals of a species including human, exhibiting minor deviation from each other are

considered normal. Individuals that show gross deviation from the normal due to congenital

malformations are known as monsters or terata.

Overall child mortality rates have shown large decreases over the past decades, in particular

from reductions in deaths from infections, diarrhoea and vaccine-preventable diseases.

Consequently, child mortality levels are now very low in many settings and policy attention is

shifting to focus on non-communicable conditions, which now make up a larger relative

proportion of all under-five deaths. In addition, in the Sustainable Development Goal era,

strategies are increasingly seeking to move beyond survival to consider morbidity and disability

outcomes, as highlighted in the Global Strategy for Women’s, Children’s and Adolescent’s

Health (2016–2030) themes-Survive, Thrive, Transform. In settings with very low levels of

communicable disease mortality, genetically determined disorders make up an important

proportion of both stillbirths and child mortality, and ongoing disability. Genetically determined

disorders can be divided into two broad groups: ‘single gene disorders’ caused by gene variants

with strong effect and ‘genetic risk factors’-gene variants with weaker effect

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The Pharma Innovation Journal http://www.thepharmajournal.com

causing disease only when combined with other genetic and/or

environmental factors.

Fig 1: Abnormal genotype or abnormal environmental conditions

Teratogenesis

Abnormal development of a terata is called Teratogenesis and

the science of development or formation of terata is

called teratology. The development of a normal individual

requires both a normal genotype and favorable environment,

therefore, teratogenesis can be due to abnormal genotype or

abnormal environmental conditions.

Fig 2: Teratogenesis in man

Teratology

Teratology is the science of studying and investigating the birth

defects and their etiologies. At birth, the incidence of the

congenital malformations amounts to 2-3%, however by the

elapse of the first neonatal year the incidence rises to about 5% [1]. On exposure to a toxic agent, a developing embryo will

exhibit a response that ranges from none to severe (i.e. death or

malformation). This response at a given dosage is sometimes

defined as teratogenic (or developmental toxic) severity and is

dependent on exposure conditions [2]. The factors that induce

congenital malformations are termed the “teratogenic factors”;

they include infectious, physical, chemical, hormonal, and

maternal health factors.

Teratogenic agents

Infectious agent

Some infections during pregnancy are teratogenic like viral

infections (e.g. rubella, herpes simplex and cytomegalovirus),

spirochetal infections (e.g. syphilis), and protozoal

infestations(e.g. toxoplasmosis). First trimester maternal

influenza exposure is reported to be associated with raised risk

of a number of non-chromosomal congenital anomalies

including neural tube defects, hydrocephalus, congenital heart

anomalies, cleft lip, digestive system abnormalities, and limb

defects [3].

Chemical agent

Medical prescription and over-the-counter drug use are

common and necessary for many pregnant women nowadays.

The principal challenge of prescribing physicians is “Will these

drugs induce teratogenic effects?” Such a drug-phobia arose

after the eruption of thalidomide teratogenicity disaster in

1960s; when the drug was used to relieve morning sickness

associated with pregnancy [6]. Most of medication exposures

during pregnancy do not carry an increased risk of congenital

malformations. Misperceptions of these risks may lead to

abrupt discontinuation of therapy and even to termination of an

otherwise wanted pregnancy.

Physical agent

Radiation is teratogenic and its effect is cumulative. The

International Commission of Radiology recommends

pregnancy Placental transporter proteins are involved in the

pharmacokinetics of drugs and have an effect on drug level and

fetal drug exposure. There is an association between P-

glycoprotein polymorphisms and the risk of fetal birth defects

induced by medications during pregnancy [7]. Six underlying

teratogenic mechanisms are stated to be associated with

medication- use. They include folate antagonism, neural crest

cell disruption, endocrine disruption, oxidative stress, vascular

disruption and specific receptor- or enzyme-mediated

teratogenesis [8]. There is a great evidence that individual

susceptibility to teratogenic drugs varies from one individual to

another, even following identical exposures. One of the factors

that may explain these individual-related variations is the

genetic makeup in the pharmacokinetics and

pharmacodynamics of the respective drugs [8].

Fig 3: Fetal Alcohol Syndrome

Maternal nicotine consumption isteratogenic leading to

increased incidence of attention hyperactivity disorder, major

depressive disorder and substance abuse in exposed children

and adolescents. Whether these syndromes are caused by

nicotine (smoke) exposure itself or by genetic and psychosocial

mechanisms is still not completely elucidated [54].

Thalidomide-induced teratogenesis

History and thalidomide embryopathy

Thalidomide was released in the late 1950’s as a nonaddic-tive,

nonbarbiturate sedative by the German pharmaceutical

company, Chemie-Grunenthal. Thalidomide was very effective

http://www.thepharmajournal.com/

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and quickly discovered to also be an effective anti-emetic and

used to treat morning sickness in pregnant women.

Thalidomide was marketed and distributed in 46 countries

around the world using different names. For example, the drug

was known as Distaval in the UK and Australia, but was called

Softenon in Europe and Contergan in. Thalidomide became

one of the world’s largest selling drugs, and was marketed

heavily and advertised as completely safe right up until it was

eventually banned in Novem-ber, 1961. Indeed, sample packets

of the drug were given out to physicians to distribute freely to

patients suffering from morning sickness. Precisely how many

women were given the drug will never be known.

Fig 4: Thalidomide

Soon after thalidomide’s release, reports surfaced of patients

developing peripheral neuropathy after taking the drug.

Reports of occurrences of severe birth defects affect-ing

multiple body systems were also coming to light, that initially

were not linked to, or were denied to be due to thalidomide. It

was not until 1961 that thalidomide was confirmed by two

independent clinicians, Lenz in Germany and McBride in

Australia, to be the cause of the largest man-made medical

disaster in history with huge numbers (over 10,000) of severe

birth defects in children. In addition, there were reports of

increased miscarriage rates during this period.

Thalidomide was subsequently withdrawn from the UK in Nov

1961 [9]and by 1962 from most of the world. As a result, the

incidence and occurrence of these severe birth defects was then

not seen Whether this disaster could have been prevented

remains unclear.

Fig 5: Structure of thalidomide enantiomers and packaging.

A: Thalidomide is a stereo-isomer and can exist in two

enantiomeric states, depending on the state of the chiral carbon

(see asterisk) allowing each form to have slightly different

structural moieties. Both enantiomers, R and S, can rapidly

interconvert (race-mize) in body fluids and tissues [10] and form

equal concentrations of each form. B: Thalidomide was

sold/distributed as a racemic mix of both enantiomers and

called “Distaval” in the UK. These images are from an actual

packet of “Distaval,” which was a Physician’s Sample and

given to women in early pregnancy.

Thalidomide-induced damage can phenocopy some other

human conditions

Fig 6: Time sensitive window of thalidomide embryopathy or the

“critical period.” Chart indicating when the major outward appearing

damage occurred in the embryo following thalidomide exposure.


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Thalidomide is antiangiogenic

Thalidomide was demonstrated in a landmark study to inhibit

angiogenic vascularization of rodent corneas induced by

fibroblast growth factor (GF) protein. This discovery led to the

suggestion that tha-lidomide might cause its teratogenic

damage by targeting embryonic blood vessels.

Angiogenesis is Essential for Embryogenesis

Blood vessels are essential for normal embryonic develop-

ment. Blood vessels supply oxygen and nutrients to grow-ing

tissues and remove unwanted waste products. During

embryogenesis, vessels form first by vasculogenesis and are

then modified into the complex vascular tree required for

embryonic and fetal growth and throughout adult life by

angiogenesis. Angiogenesis [11] is where the primitive vessels

formed by vasculogenesis are elabo-rated upon where

endothelial cells in the existing vessels proliferate and migrate

to avascular areas in response to signals, including hypoxia or

vascular endothelial growth factor. Once a new vessel tube has

been made, the vascular tube recruits vascular smooth muscle

cells, which stabilize the vessel. The smooth muscle coating is

lost to allow endothelial cells to proliferate and migrate into

new regions if signaled to do so.

Angiogenesis is essential for embryogenesis

Fig 7: Embryonic limb development.

In humans the upper limbs form around a day earlier (day 26)

than the lower limbs (day 27). The limb bud consists of two

key signaling centers. The apical ectodermal ridge (AER), a

thickened epithelium lining the distal tip of the bud and

separating the dorsal from ventral surface; and the zone of

polarizing activity (ZPA) in the posterior-distal mesenhcyme.

The AER expresses which signals to the mesenchyme to induce

Fgf10 and to the ZPA to induce and maintain Shh, which itself

feeds back to maintain [12-15]. This feedback loop maintains cell

proliferation and limb outgrowth and induces other genes, for

example the Hox genes, which establish the pattern of the limb

elements, humerus, radius, ulna, and handplate, as well as the

soft tissues. The limbs grow out from specific regions of the

flank of the embryo and as the limb grows out the limb is

patterned proximally to distal, that is, humerus/femur are laid

down before the radius, ulna/fibular, tibia, and then the

handplate/footplate.

vessels are rapidly changing throughout embryogenesis and

organogenesis to accommodate the changes and growth of the

embryo.

Blood vessels are essential for normal embryonic devel-

opment, and vessel loss or disruption can unsurprisingly result

in death or birth defect.

Angiogenesis is targated by thalidomide in embryotic

Development and in Adults

Thalidomide has multiple actions in the adult body and causes

a variety and range of damage in the embryo. To determine

how and which of its activities actually cause teratogenesis,

stable, structural analogs of thalidomide were screened to

determine their function, confirm which aspect of thalidomide

action, antiangiogenesis or antiin-flammation, results in

teratogenesis, and study the result-ing damage to gain insights

into how the drug causes birth defect.

Why are some vessels targated while others are apparently

unharmed

Blood vessels undergoing angiogenesis lose their vascular

smooth muscle coats to allow endothelial cells to proliferate

and migrate to form new tubes. Vessels with smooth muscle

coats are quiescent and not undergoing angiogenesis. Using in-

vitro rat and mouse aortic ring culture assays, CPS49 was dem-

onstrated to destroy vessels without smooth muscle, but blood

vessels possessing smooth muscle coats were pro-tected. This

indicates that newly formed and forming blood vessels without

smooth muscle coats could be susceptible to thalidomide. In

the chicken embryo at the time the drugs are applied to the

embryo,

Fig 8: How does thalidomide induce Phocomelia?

Molecular targets of thalidomide

Much is known about thalidomide’s mechanism of action

underlying its anti-inflammatory and anti-myeloma activ-ities

in human adults, than its teratogenic activities. Thali-domide

inhibits TNF-a expression rapidly, vital for the inflammatory

response. However, new targets have been identified and

linked to thalidomide teratogenesis, though how these targets

cause the embryonic damage still remains unclear.

Tubulin: An analog of thalidomide, 5HPP-33, can bind

tubulin, which was demonstrated through crystal structure

binding assays. Tubulin is part of the cyto-skeleton, and,is

required in cell proliferation, which is essential for

angiogenesis and formation of new vessels in the embryo. This

study demonstrated that tubulin is bound by the 5HPP-33

thalidomide analog and cytos-keletal dynamics are altered

preventing cell division. In the time-sensitive window many

organs/tissues are under-going growth and maturation and

could be affected in this manner, either directly or through loss

of vessels, resulting in hypoxia and cell death. This work

supports that of other studies which showed disruption of actin

cytoskeleton [16].


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Fig 9: Framework of thalidomide induced embryonic damage.

This frame-work incorporates the majority of the previously

proposed models/hypotheses to attempt to provide an

explanation for thalidomide embryopathy. Thalido-mide

and/or a breakdown product after binding a molecular target

acts nega-tively on smooth muscle negative blood vessels,

likely affecting the actin cytoskeleton of the endothelial cells,

and preventing their proliferation and migration into avascular

regions, causing oxidative stress, cell death, and gene

expression loss, resulting in tissue damage. In rapidly

developing tissues and organs, such as the limbs and internal

organs, this would be devastating, causing tissue loss or tissue

function loss, preventing growth. The damaged or missing

tissues would then also fail to properly recruit and pattern

proper chrondrogenesis, nerve innervation, muscle patterning,

etc., exacerbating the condition and damage.

Biomolecular Mechanisms in Teratogenesis

The most common mechanisms of action of terato-gens are

hyperacetylation, cholesterol imbalance, alteration of folate

metabolism [17-20] and folate antagonism, retinoic acid

imbalance, endocrine disruption, vascular disruption and

oxidative stress.

Conceptus development stage

Organisms present distinct sensitivity to external agents

according to their gestational age. A conceptus is a fertilized

egg cell until the 3rd week of gestation. The period from the 3rd

to the 8th week it is called embryonic phase, and from the 9th

week onward the fetal phase.

Fig 10.1: - Teratogenesis pathways due to oxidative stress

Fig 10.2: Critical stages of human embryological development

The two initial weeks after fertilization, in which the zygote is

undergoing mitotic cell division is called the ‘all-or-nothing’

phase; in case a contact with a teratogenic agent occurs, it can

result either in spontaneous abortion or in a normal embryo-

fetal development. If teratogenic expo-sure occurs between the

3rd and 8th week of gestation, a pe-riod in which most of the

morphological structures develop, it can lead to considerable

phenotypical changes in the em-bryo, such as alterations in the

central nervous system, limbs and face. From the 9th week of

gestation some organs are still developing, like external

genitalia and brain, and exposure to teratogens can culminate

in functional abnor-malities. However most morphological

characteristics are preserved from this phase onward.

Fig 11: Potential maternal and fetal determinants of risk


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Upper panel: effect of a genetic deficiency in maternal

glucuronidation on benzo[a]pyr-ene-initiated in utero

resorptions (fetal death). Pregnant mutant Gunn rats with a

hereditary deficiency in the UDP-glucuronosyltransferase

(UGT) 1 family, or the parent Wistar strain with normal UGT

activity, were treated with benzo[a]pyrene (25 mg/kg ip) or its

corn oil vehicle (control) on gestational day (GD) 10. Dams

were killed on GD 20 for examination of the uterus and fetuses.

Implantations include resorptions and fetuses delivered alive.

Asterisks indicate a difference from Wistar rats with the same

treatment, and the plus symbol indicates a difference from the

Gunn control group (P< 0.05). Lower panel: Interindividual

variability in the activity of glucose-6-phosphate

dehydrogenase (G6PD) in amniocytes obtained from human

subjects. Fetal amniocytes were obtained from term amniotic

membranes of volunteer mothers who had (n = 8) or had not (n

= 5) taken an anticonvulsant drug throughout pregnancy. Of

those women taking anticonvulsants, 4 took phenytoin, 2 took

phenobarbital, 1 took carbamazepine and 1 took phenytoin plus

primidone. No correlation was apparent between

anticonvulsant exposure and G6PD activity. Cells were

cultured to confluency, aliquotted and kept frozen until assayed

for G6PD activity. For each subject, 4 amniocyte aliquots were

homogenized in PBS buffer (pH 7.4), sonicated for 5 min to

ensure membrane lysis and analyzed [21] as described

elsewhere. All results were standardized with respect to total

protein content and reported in International Units (U) per gram

(g) of protein (U/g). Values represent the mean T SD.

Fig 12: Postulated interactions between the pathways for formation

of reactive oxygen species (ROS) and reactive nitrogen species

(RNS).

Among the nitric oxide synthases (NOSs), inducible nitric

oxide synthase (iNOS) appears to be expressed during

organogenesis only in extra-embryonic (ectoplacental cone)

and maternal tissues, producing relatively stable nitric oxide

that diffuses into the embryo where it reacts with

embryonically generated superoxide anion to produce highly

reactive peroxynitrite (see text). The embryopathic roles of the

neuronal and endothelial forms of NOS have yet to be shown.

Among other reactions, peroxynitrite can initiate oxidative

damage to cellular macromolecules, oxidize soluble (e.g. GSH)

and protein thiols, cause the nitration of aromatic amino acids

(tyrosine, tryptophan, phenylalanine) in proteins and similarly

cause the nitration and in some cases deamination of DNA

bases (e.g. guanine, adenine), all of which could have

embryopathic [22] consequences.

Fig 13: Xenobiotic bioactivation by prostaglandin H synthases

(PHSs) and lipoxygenases (LPOs).

List of Teratogenic Drugs Used in Dermatology

1. Acitretin (Soriatane®)

2. Finasteride (Propecia®) *

3. Fluorouracil (Fluoroplex®, Efudex®)

4. Griseofulvin (Grifulvin® V, Fulvicin®, Gris-Peg®,

Grisactin®)

5. Goserelin (Zoladex®)

6. Isotretinoin (Accutane)

7. Methotrexate †

8. Podophyllin/podophyllum (Podocon®-25)

9. Stanozolol (Winstrol®)

10. Tazarotene (Tazorac®)

11.Thalidomide (Thalomid®) †

Pregnancy Labeling for Prescription Drugs:

Historical Perspective

September 12, 2007 marks the tenth anniversary of a public

hearing that was hoped to be the death knell of the pregnancy

labeling categories for pharmaceuticals, the A, B, C, D, X

system of designations that was put in place by the US Food

and Drug Administration (FDA) in 1979 (US FDA, 1979). The

replacement of the pregnancy labeling categories had been

sought by the Public Affairs Committee of the Teratology

Society, and the public hearing that was believed to herald the

impending de-mise of the system in 1997 was seen as an

important public health advance. On this tenth anniversary, the

sys-tem remains in place, although some progress has been

made in replacing [23] it. We examine here the history of and

rationale behind the effort to change the pregnancy label and

the current status of proposed new labeling, and we offer

recommendations for the future.

The first public affairs committee position paper

Teratology Society members who counseled patients on drug

use during pregnancy did not find the categories to be helpful.

In fact, it was the opinion of many clini-cians that the inflexible

use of prescribed language in pregnancy categories created

patient and physician anxi-ety, which was compounded by the

assumption that the categories represented a gradation of risk


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[24]. The lack of in-formation about the nature, severity, timing,

or treatabil-ity of the putative fetal damage that resulted in a

Cate-gory D or X classification was also viewed as a shortcom-

ing of the pregnancy categories [25-29].

Table 1: Drugs/Chemical

Agent/Drug/Chemical Risk Fetal effects Fetal risks Maternal risks

Prescribed or street drugs

Ethanol D/X FAES:IUGR, MR, microcephaly, 40% risk of FAES –

characteristic facies, CHD, joint, 6 drinks/day

skeletal, dermal

Cocaine C/X IUGR, cerebral infarction, bowel Fetal death Abruption placenta

atresia, heart, limb, facial, GU tract,

vascular disruption

Toluene X Toluene embryopathy similar to FAS Maternal inhalation 10–100 –

times occupational exposure

Table 2: Characterization of teratogenic effects*

General effects

Alterations of morphogenesis

Alterations of CNS function

Other functional impairments

Death of the conceptus, embryo, or fetus

Prenatal-onset growth deficiency

Carcinogenesis

Specific effects

Recognizable syndrome

Other distinctive features

Magnitude of risk

Absolute

Relative

Prenatal diagnosis

Detailed ultrasound examination

Amniocentesis or other invasive method

Availability, Reliability

Utilty

Table 3: Characterization of teratogenic exposures*

Agent

Nature of the chemical, physical or infectious agent Inherent

developmental toxicity

Capacity to produce other kinds of toxicity in the mother Dosage to

embryo or fetus

Single, repeated, or chronic exposure Duration of exposure

Maternal dose

Maternal route of exposure Maternal absorption

Maternal metabolism and clearance Placental transfer

Period of pregnancy

Between conception and onset of embryogenesis Embryogenesis

Fetal period Other factors

Genetic susceptibility of mother Genetic susceptibility of the fetus

Other concurrent exposures

Maternal illness or other condition associated with exposure

Availability of tests to quantify the magnitude of maternal exposure

Primary prevention of congenital anomalies

Purpose of the recommendations Most congenital anomalies are rare and form an important

group of Rare Diseases, for which EU Member States are

developing National Plans. Primary prevention of congenital

anomalies was identified as an important action in the field of

Rare Diseases in the Communication from the Commission to

the European Parliament, the Council, the European economic

and social committee and the committee of the regions of 11th

November 2008. However, it has not been included in the

Council Recommendation on an action in the field of rare

diseases of 8th June 2009. This document aims at providing an

outline of evidence-based policy actions for primary

prevention of congenital anomalies. It does not seek to

recommend specific policy options, rather to indicate the areas

that Member States could target in their strategies for Primary

Prevention of congenital anomalies. EUROPLAN [1] will

support and facilitate Member States to incorporate the

recommendations specified here in their National Plans, and

will facilitate exchange of experience among Member States,

in collaboration with EUROCAT [2].

The scope of policy actions needed for primary prevention

of congenital anomalies

In the field of medicinal drugs

to advise women taking

medication to seek medical advice before trying to get

pregnant [4];

to ensure that guidelines are, or are going to be, made

available for physicians regarding risk-benefit balance for

use of medications in pregnancy, particularly those

medications used for treating chronic diseases [5];

to provide a teratogen information service where

specialized advice can be sought by women and

professionals [6];

to conduct postmarketing pharmacovigilance to detect any

risk of congenital anomalies associated with use of

medications, with the support of population-based

congenital anomaly registries [7].

In the field of food/nutrition and lifestyle

to improve folate status through periconceptional

supplementation with folic acid, promotion of the

consumption of foods rich in natural folates, and the

appropriate use of fortified foods [8].

to prevent overweight/obesity and underweight [9, 11];

to promote effective information on diet and nutrition in

women at childbearing age, minimizing the risks of

deficiency and/or overdosing of vitamins and essential

trace elements(12);further to the implementation of EU food

safety strategies, to prevent food contamination by

recognized developmental toxicants [13];

to reduce active and passive smoking [14];

to promote alcohol avoidance in women who are pregnant

or wishing to get pregnant [15, 18].

to pay special attention to diet and lifestyles in

communities with low socio-economic status or of recent

immigrants.

In the field of health services

to make available preconceptional care including genetic

testing and counselling for families at risk [19];


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to ensure that women with diabetes, epilepsy and other

chronic diseases receive preconceptional care in order to

minimize the risk of congenital anomalies [20];

to ensure evidence based vaccination policies to ensure

women are protected against infectious diseases associated

with congenital anomalies and avoid contraindicated

vaccinations during pregnancy [21];

to include in school educational programs the awareness

that congenital anomalies may be caused very early in

pregnancy, often before the pregnancy is confirmed, and

hence healthy practices should start preconceptionally;

to include consideration of specific pregnancy-related

actions in public health action plans on all the major health

determinants.

In the field of environmental pollution including the

workplace

Further to the implementation of EU policies on high-

concern chemicals, to ensure both regulatory actions and

risk.

communication towards citizens in order to minimize

exposure to pollutants identified as teratogens [22];

to ensure a suitable surveillance system where

environmental risks can be identified through the

integration of congenital anomaly registers with

developments in biomonitoring [23];

to minimize exposure of pregnant workers in their

workplace to risk factors for congenital anomalies

(chemical, physical and biological) [24].

Types of primary preventive actions and their effectiveness

A number of types of primary preventive action can be

identified:

1. Advice to future parents by health professionals during

individual preconceptional and early pregnancy

consultations, tailored for high and “low” (average

population) risk couples.

2. Health education campaigns targeted to potential future

parents.

3. EU-based and/or national regulatory actions which affect

risk factors at source such as medicines, chemicals,

infectious agents, foods, tobacco and alcohol and other

recreational drugs.

4. Surveillance, research and evaluation generating evidence

for the initiation or updating of primary preventive

measures. This includes also the establishment of expert

committees to review evidence.

The effectiveness of targeted actions towards primary

prevention of congenital anomalies is expected to be

markedly improved by

an integrated primary prevention plan involving all

relevant health professionals, thus avoiding isolated and/or

uncoordinated actions/recommendations;

Implementation and refinement of EU food and

environmental control programs providing special

attention to congenital anomaly risk factors;

proper evaluation and integration of new scientific

knowledge into public health actions;

ensuring preconception health

care in local public

health programs [25, 29], while recognizing that many

pregnancies are unplanned;

availability of epidemiological surveillance data from

population-based congenital anomaly registers, to monitor

the effectiveness of services and interventions to build a

sound evidence base for policy development planning and

action;

to ensure sustainability through national and international

funding.

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